W. Archie Bleyer

The clinical pharmacology of methotrexate. new applications of an old drug

Methotrexate is now used widely for the treatment of acute leukemia, non‐Hodgkins lymphoma, osteogenic sarcoma, choriocarcinoma, breast carcinoma, pulmonary and epidermoid carcinoma, and intrathecal chemotherapy. It is also useful in bone marrow transplantation, severe psoriasis, rheumatoid arthritis, dermatomyositis, Wegeners granulomatosis and sarcoidosis. The recent dramatic intensification of methotrexate therapy can be attributed in part to advances in our understanding of the clinical pharmacology of the folate antagonists, as well as to the combination of positive results and their effective dissemination to medical oncologists. The review summarizes the pharmacologic findings and illustrates how they are currently being applied to the treatment of malignant disease.

National cancer clinical trials: Children have equal access; adolescents do not

PURPOSE To determine whether adolescents with cancer, who in comparison to younger patients have a higher cancer incidence and lower mortality reduction, have equal access to national cancer clinical trials. METHODS The ethnic/racial distribution of 29,859 subjects < 20 years of age entered onto National Cancer Institute-sponsored clinical trials between January 1, 1991, and June 30, 1994, was compared with the expected distribution of patients of the same age in the United States. RESULTS The Childrens Cancer Group and Pediatric Oncology Group had 29,134 (97.6%) of the total study entries among < 20-year-old subjects during the 3.5 years of surveillance. The adult cooperative groups accounted for < 3% of the clinical trials entries in the 15-19-year age range. When analyzed nationally by region, the under-representation of the older adolescent subjects was universal. From other analyses, the two pediatric cooperative groups were estimated to have registered > 94% of the children < 15 years of age who were expected to have been diagnosed to have cancer, but only 21% of the cancer patients in the 15-19-year age group. CONCLUSIONS The national pediatric cancer cooperative groups allow the majority of American children < 15 years of age and their families equal opportunity to access clinical cancer trials, regardless of race or ethnicity. Among patients 15-19 years of age, however, > 75% are not being enrolled by any cooperative group sponsored by the National Cancer Institute. Thus, older adolescents are disadvantaged with respect to access to the national clinical trials, regardless of their race or ethnicity.

Obesity and Outcome in Pediatric Acute Lymphoblastic Leukemia

PURPOSE To evaluate the effect of obesity (defined as a body mass index > 95th percentile for age and sex at diagnosis) on outcome of pediatric acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS We retrospectively analyzed data from 4,260 patients with newly diagnosed ALL enrolled from 1988 to 1995 onto five concurrent Childrens Cancer Group studies. Results were verified in a second cohort of 1,733 patients enrolled onto a sixth study from 1996 to 2002. RESULTS The 1988 to 1995 cohort included 343 obese and 3,971 nonobese patients. The 5-year event-free survival rate and risk of relapse in obese versus nonobese patients were 72% +/- 2.4% v 77% +/- 0.6% (P = .02) and 26 +/- 2.4 v 20 +/- 0.6 (P = .02), respectively. After adjusting for other prognostic variables, obesitys hazard ratios (HRs) of events and relapses were 1.36 (95% CI, 1.04 to 1.77; P = .021) and 1.29 (95% CI, 1.02 to 1.56; P = .04), respectively. The effect of obesity was prominent in the 1,003 patients > or = 10 years old at diagnosis; in this subset, obesitys adjusted HRs of events and relapses were 1.5 (95% CI, 1.1 to 2.1; P = .009) and 1.5 (95% CI, 1.2 to 2.1; P = .013), respectively. In a second cohort of 1,160 patients 10 years old, obesitys adjusted HRs of events and relapses were 1.42 (95% CI, 1.03 to 1.96; P = .032) and 1.65 (95% CI, 1.13 to 2.41; P = .009), respectively. The effect of obesity on outcome was unrelated to changes in chemotherapy doses, length of intervals between chemotherapy cycles, or incidence and severity of therapy-related toxicity. CONCLUSION Obesity at diagnosis independently predicts likelihood of relapse and cure in preteenagers and adolescents with ALL.

INTENSIVE THERAPY FOR CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKAEMIA AND UNFAVOURABLE PRESENTING FEATURES: Early Conclusions of Study CCG-106 by the Childrens Cancer Study Group

229 children with acute lymphoblastic leukaemia (ALL) and with clinical and laboratory features associated with a high risk of treatment failure entered a randomised study of three treatment regimens. Before 1981, such patients had a 3-year event-free survival (EFS) of 47%. Two intensive therapies, the Berlin-Frankfurt-Munster (BFM) 76/79 regimen and the New York (NY) regimen were compared with a control regimen that had achieved the best outcome in previous Trials. Data on 214 cases (93.4%) were analysed. The 3-year EFS was 78% for the BFM and NY regimens and 49% for the control regimen, a significant difference. The differences persisted after stratification by age at onset, sex, white blood cell count at diagnosis, and marrow blast morphology. Control patients were 2.7 times more likely to fail induction, to die, or to relapse than were patients on the intensive regimens.

Central Nervous System Leukemia

With one exception, the risk and severity of neurotoxicity is directly proportional to the number of therapeutic modalities used. Three are worse than two, and two are worse than one. Combinations of therapeutic modalities which include CNS RT appear to be the most neurotoxic. The least neurotoxic combination of two modalities appears to be the IT MTX with high-dose intravenous MTX. Thus far, high-dose MTX appear to be the safest single modality, in terms of acute, subacute, and delayed neurotoxicity. The improved outcome in intellectual and academic performance in the NCI-191/CCG-134P conjoint trial of the CCSG and the Pediatric Branch described above (see section of Presymptomatic CNS Therapy) appears to confirm this observation. Whether triple IT chemotherapy will have the same result remains to be established. If CNS RT must be combined with MTX therapy, the least neurotoxic approach appears to be to administer these modalities in sequence, IT MTX, or high-dose intravenous MTX followed by CNS RT. MTX given during or after CNS RT appears from the clinical data to be more likely to produce severe neurologic sequelae. An ultimate goal would be to avoid both ionizing RT and IT chemotherapy. To this end, the NCI/CCSG study has demonstrated that this may be possible, except for those patients who are at the highest risk for CNS relapse despite conventional CNS prophylaxis. Meanwhile, for presymptomatic therapy, either cranial RT (18 Gy total dose at 120-180 cGy per day) in conjunction with IT MTX, or frequent IT chemotherapy with MTX, cytarabine, and hydrocortisone combined and administered throughout induction, consolidation, and maintenance is eminently justified in the majority of children with ALL. On a worldwide basis, chemoradiotherapy with cranial RT and IT MTX remains the established method of preventing overt CNS leukemia. The benefits of this intervention, in terms of prevention of symptomatic CNS leukemia, prolongation of complete remission, and increased cure rates, are clearly worth the risks.

IRRADIATION, METHOTREXATE TOXICITY, AND THE TREATMENT OF MENINGEAL LEUKÆMIA

Abstract 31 patients with meningeal leukaemia were randomised to therapy with intrathecal methotrexate with and without 2400r to the cranial vault. Remissions were achieved in 29 patients. Remission duration was significantly longer (234 + days) in the group receiving methotrexate alone than in those receiving methotrexate and irradiation (125 days). A spectrum of methotrexate toxicity was seen after intrathecal administration ranging in severity from chemical arachnoiditis which was common (17 patients) through transient paresis (1 patient) to encephalopathy (2 patients). These toxicities were just as common in patients receiving preservative-free methotrexate as in those receiving methotrexate with preservative, and therefore should be ascribed to direct toxic effects of methotrexate itself or its breakdown products rather than preservative. The neurotoxicity of methotrexate must be taken into account in evaluating the risks and benefits of the therapy for meningeal leukaemia.

The effect of photon irradiation on blood-brain barrier permeability to methotrexate in mice.

Methotrexate was administered by intraperitoneal injection (100 mg/kg) to unirradiated mice, and to mice receiving varying doses of cranial irradiation. The animals were sacrificed 24 hours after injection, and methotrexate assays were performed on brain tissue. No methotrexate was detected in the brains of the unirradiated animals. Detectable levels of methotrexate were present after 2000 rad cranial irradiation, but not after 500 rad, 1000 rad, or 1500 rad. The implications of these findings are discussed.

New vistas for leucovorin in cancer chemotherapy.

With a resurgence of interest in leucovorin calcium (LV), many questions about its role in cancer chemotherapy are being asked again. How does it modulate 5‐fluorouracil (5‐FU) therapy? Can it potentiate the cytotoxicity of 5‐FU more in malignant than in normal cells? Does it rescue tumor cells from high‐dose methotrexate (MTX) more than it does normal cells? How should LV rescue be individualized to maximize the therapeutic index? When can LV be administered orally, and how can LV rescue be conducted at home? When is LV rescue necessary, and what toxicities occur when it is inadequate? Some answers to these questions are provided in this review.With a resurgence of interest in leucovorin calcium (LV), many questions about its role in cancer chemotherapy are being asked again. How does it modulate 5-fluorouracil (5-FU) therapy? Can it potentiate the cytotoxicity of 5-FU more in malignant than in normal cells? Does it rescue tumor cells from high-dose methotrexate (MTX) more than it does normal cells? How should LV rescue be individualized to maximize the therapeutic index? When can LV be administered orally, and how can LV rescue be conducted at home? When is LV rescue necessary, and what toxicities occur when it is inadequate? Some answers to these questions are provided in this review.

What can be learned about childhood cancer from "Cancer statistics review 1973-1988".

Background. National data on childhood cancer is becoming more available, but there continues to be a paucity of information.

Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: A report from the intergroup rhabdomyosarcoma study group

Purpose This study was designed to estimate the partial and complete response rates (CR and PR) of two novel drug pairs (vincristine and melphalan vs. ifosfamide and etoposide) and to improve overall survival of previously untreated patients with metastatic rhabdomyosarcoma. Patients and Methods One hundred twenty-eight patients were randomly assigned to phase II window therapy consisting of vincristine and melphalan (VM-containing regimen) or ifosfamide and etoposide (IE-containing regimen). Brief window therapy (12 wks) was immediately followed-up by vincristine, dactinomycin, and cyclophosphamide (VAC), chemotherapy, surgery, and irradiation, with continuation of either VM or IE in patients with initial response. Major endpoints were initial CR and PR rates after the phase II window phase of therapy, failure-free survival (FFS), and survival. Results Patients who received the VM-containing regimen experienced significantly more anemia, neutropenia, thrombocytopenia, and had more cyclophosphamide dose reductions. The initial PR and CR rates were not significantly different for patients treated with either regimen (VM, 74%; IE, 79%;P = 0.428). However, FFS and overall survival (OS) at 3 years were significantly better with the IE-containing regimen (FFS: 33% vs. 19%;P = 0.043; OS: 55% vs. 27%;P = 0.012). Conclusions Although the VM-containing regimen produced a high response rate, inclusion of melphalan appeared to limit the cyclophosphamide dose that could be administered, and ultimately, this regimen was associated with a significantly worse outcome than was the IE-containing regimen. Also, the IE-containing regimen was associated with a gratifyingly high survival rate at 3 years (55%), which is significantly higher than has been observed on any previous Intergroup Rhabdomyosarcoma Study Group regimen for similar patients. We believe that this promising outcome indicates that this drug pair merits further randomized testing in metastatic rhabdomyosarcoma.